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Anaphylaxis to muscle relaxants: Cross-sensitivity studied by radioimmunoassays compared to intradermal tests in 34 cases
Anaphylaxis to muscle relaxants: Cross-sensitivity studied by radioimmunoassays compared to intradermal tests in 34 cases D. A. Moneret-Vautrin, MD,* J. L. Gukant, MD, DSc,** L. Kamel, MSc,** M. C. Laxenaire, MD,*** S. El Kholty, MSc,** and J. P. Nicolas, MD** Nancy,
France
Thirty-four patients (31 female and three male patients) with a previous anaphylactoid shock to muscle relaxants were investigated. The seric antimyorelaxant IgE was detected by radioimmunoassay (RIA), and the results were compared to intradermal test (IDR) reactions to dilutions of the commercial drugs. The RIA was carried out with a Sepharose-myorelaxant solid phase and anti-IgE “‘I-labeled IgG. The results corresponded to the percentage of labeled anti-IgE bound on the solid phase. The RIA with Sepharose-alcuronium and Sepharose-choline was estimated positive from determination with normal sera (n = 12) when bound IgE was >I .O% and I .5%, respectively. The RIA and IDR were positive in 43.5% and 758, respectively, of the cases, with a concordance of 66%. One test at least was positive in 79.4% of the cases. No correlation was found between IgE seric levels and the RIA nor between the cutaneous sensitivity and the RIA. Cross-reactivity with Sepharose-choline and Sepharose-alcuronium was observed in 50%, and it was demonstrated by IDR in only 34.2%. The RIA demonstrated the specificity of IgE to quaternary ammonium compounds as myorelaxant drugs. The positive IDR revealed the bridging of mast cell-bound spectfic IgE, depending on structural conditions, such as the flexibility of the molecules or the variable spectficity of the antibodies, restricted to quaternary ammonium ions or enlarged to a broader part of the incriminated molecules. (J ALLERGY CLIN IMMUNOL 1988;82:745-52.)
The incidence of ASs in general anesthesia is 0.67% with death in 0.05%.lm3 The following muscle relaxants are predominantly implicated: D-tubocurarine, alcuronium, gallamine, succinylcholine, pancuronium, vecuronium, and, more recently, atracurium.4-” Alcuronium is mostly involved in Australia, whereas ASS are mostly provoked by suxamethonium in France. *, 3. 9, ‘* The histamine-releasing property of these drugs is well-known. In some cases, a nonspecific activation of the alternate pathway of complement has been speculated, but the anaphylactic mechanism is more frequent. ‘345 The passive cutaneous
From *Service d’Immuno-Allergologie, Mtdecine D, Nancy, **Laboratoire de Biochimie Medicale et Wdiatrique - Faculte de MCdecine, Nancy, and ***Dtpartement d’Anesth&iologie, Hapital Central, Nancy, France. Received for publication Nov. 17, 1986. Accepted for publication April 23, 1988. Reprint requests: D. A. Moneret-Vautrin, MD, Faculte de M&ktine, B.P. 184, 54505 Vkndoeuvre, Les, Nancy Cedex, France.
Abbreviations used IDR: Intradermal test RIA: Radioimmunoassay
AS: Anaphylactic shock
anaphylaxis test is often positive, and its reactivity is abolished by heating serum 2 hours at 56” C.5-8 Leukocyte histamine release is inhibited by preincubation with an anti-IgE serum. I3 The presence of sericspecific IgE against myorelaxants has been demonstrated by Baldo and FisheP’* and Harle et alL9-*’ All molecules of the muscle relaxants share quaternary ammonium radicals that should be the common epitopes. This could explain the cross-reactivity among those drugs. In patients with AS to one myorelaxant, the number of drugs implicated in the crossreactivity is variable when IDRs are used.*‘. 23 The comparison of IDRs and RIAs has revealed that the in vitro cross-reactivity is not related to the clinical 745
746
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J. ALLERGY Ciirv IMMUNCL. NOV’MBER :x48
et al.
Sepharose -ethanolamine
iepharose 3lcuronium
Sspharosa choline
vecuronium have similar structures except the presence of two quatemary ammonium in pancuronium, whereas vccuronium hasonly one quatemary ammonium and one tertiary. The diagnosis has been establishedfrom 6 tc; 12 weeks after the AS in 28 casesand from 3 to 10 year.” xfttcr the AS in six cases.
------. .
The IDRs were performed in the back with serial dliutlons of commercial solutions and 0.03 to 0.05 ml peg injection. The IDR was considered positive when the diameter of ihc: wheal reached 10 mm 1.5minutes after Ihe injection ’
RIA . . : .. . : .. . : l
.
:
.
Controls
ln=ZO)
c
patients
lnz26)
FIG. 1. Percentage of uptake of ‘251-labeled anti-lgE onto Sepharose-choline and Sepharose-alcuronium in the presence of control sera (*I. The unspecific adsorption of the tracer was also tested for sera from patients (0) with Sapharose-ethanolamine instead of the drug-solid phase. The upper normal limit of uptake percentage (- -- -) was estimated, respectively, to 1.0% and to 2.0% for Sepharose-alcuronium and Sepharose-choline.
Specific antidrug IgE was detected in serum by an RlA in which the drug (alcuronium or choline) was r~ovalentlv coupled to Sepharose. Drug-Sepharose
coupling
procedure.
PATWWS
AND METHODS
Thirty-four patients (31 female and three male patients, aged from 16 to 67 years) have been included in the study. The myorelaxant and number of patients implicated were succinykholine, 19; gallamine, 2; alcuronium, 5; pancnronium, 5; and vecuronium, 3. The first two myorelaxants have a closed chemical structure, since two methylcholine residuesare included in succinylcholineand three ethylcholine residuesin the structure of gallamine. Pancuronium and
oi
solid drug phase was washed successively with threefold the volume of 0.1 mol/L of sodium carbonate, pW 12, ISfold the volume of 0.1 mol/L of sodium borate buffer, pH 9.0, and incubated (overnight with 10 ml of 1 mol:L of ethanolamine at pH 9.0 and at 35” C. Then, it was washed again with 15-fold the volume of 0.1 moliL of sodium borate buffer, pH 9.~0. 15fold the volume of 0 05 mol/ I, of sodium acetate, pH 4.0, and 15fold of 0.154 mol ‘L of NaCl containing 0.02% NaN, (wt/vol). The efficiency of’ the coupling procedure was estimated to about 20% and 25% for alcuronium dichloride and choline. respectively.
This was calculated, from drug content of risk of anaphylactoid reactions.*’ In the present study, we have determined seric-specific IgE against muscle relaxants by IDR and RIA in 34 patients who had an AS to succinylcholine ( 19)) gallamine (2)) alcuronium (5), pancuronium (4), and vecuronium (4). Our purpose was (1) to compare the clinical value of RIA and IDR in the diagnosis of AS to two myorelaxants, succinylcboline and alcuronium, and (2) to evaluate the accuracy of both tests in cross-reactivity to other muscle relaxants, since both tests investigate different aspects of the IgE mechanism.
One Barn
epoxy-activated Sepharose6B (PharmaciaFine Chemicals, Uppsala, Sweden) was swollen in distilled water and WC-. cessivelywashed with tenfold the volume of 0. I moli L of sodium carbonate, pH 12, containing 0.5 mol/L of NaCI. The gel was incubated with 70 mg of either alcuronium dichloride (Hoffmann-LaRoche, Basel, Switzerland) or choline chloride (Sigma Chemical Co., St. Louis, MO.) during 18 hours under mild. rotative agitation and at .3tr” C. The
the supernatant
before and after the coupling with ultraviolet spectrophotometry. Radioimmunoassay. Each test was duplicated. ‘4 volume of 50 ~1 of drug phase was incubated overnight with 50 p,I of serum at room temperature. The gel was washed three time with 3.0 ml of 0.1 mol/L of sodium phosphate buffer, pH 7.4, containing 0.154 mol/L of NaCl, 0.02% bovine serum albumin (wtivol), and Tween 20, and incubated during 12 hours with 50 ~1 of ‘*Wabeled anti-IgE (Pharmacia). It was then washed three times again with the sodium phosphate solution. The presence of seric-specific antidrug IgE was attested from the percentage of bound labeled antiIgE determined by counting the radioactivity. .The nonspecific binding of seric IgE was tested with Sepharoscethanolamine instead of the solid drug phase, and the nonspecific binding of anti-IgE was tested by subrtltution of serum with a 0.1 mol /L of sodium phosphate buffer solution containing 2% bovine serum albumin (wt/vol).
RESULTS The cardiovascular collapse was observed in all cases with cutaneous reactions involving erythema or
VOLUME 82 NUMBER 5, PART 1
Anaphylaxis
TABLE I. IDR and RIA to the incriminated (19), gallamine (2), and alcuronium (5)
myorelaxant
in 26 patients
with
AS
to muscle
Incriminated myorelaxant*
1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16
17 18 19 20 21 22 23 ’ 24 25 26
I
C C C C C C C C C C C C C C C C C C C G G
A A A A A
hE (KUI/L) ND 572 190 203 80 ND ND 303 57 ND 39 80 ND ND 55 21 ND 27 ND 15 12 367 870 ND 921 ND
I* 1
IDR (pglml)
(1) (10) (10) (10) (10) (100) (1W (1W ++ + ++ + + + + + + + -
(0.1) (10) (0.01) (10) (10) (10) (10) (10)
(0.5) (50)
747
to succinylcholine
Incriminated
Case
relaxants
myorelaxant RlAt (.c)
(%I
+ -
(25.9) (1.5) (1.5) ND (1.0) (1.1)
+ + + -
+ + + + + + -
(1.8) (13.4) (0.4) (0.3)
(1.6) (2.4) (3.1)
(1.2) (3.3) (0.5) (2.5) (28.8) (16.4) (1.0) (0.67) (1.1) (1.1) (0.7) (0.9)
(0.8)
ND = Not done. *C = Succinylcholine; G = gallamine; A = alcuronium. YThe radioimmunoassay was carried out with Sepharose-choline for the diagnosis of anaphylaxis to succinylcholine and gallamine, and with Sepharose-alcuronium for the diagnosis of anaphylaxis to alcuronium. The upper limit of normal values was estimated, respectively, to 2.0% and to 1 .O% for the Sepharose-choline and sepharose-akuronium RIA.
Quincke’s edema in 80% of cases and bronchospasm in 39% of cases. Previous anesthesia was reported in 23 cases. Four patients had never been anesthetized. Two patients had never received vecuronium that elicited the AS. Atopy was observed in 33% of cases and confirmed by IDR with inhalants; 24% of patients had extrinsic asthma in childhood. Three other subjects have an infraclinical atopy, revealed by positive skin tests to inhalants and a high level of seric IgE (367,772, and 921 KUl/L). In the 20 control subjects, the percentage of binding was 0.6 + 0.2%, 0.5 + 0.2%, and 1.0 + 0.5%, respectively, with Sepharose-ethanolamine, sepharose-alcuronium, and Sepharose-choline. The upper normal limit was estimated to 1 .O% and to 2.0% for Sepharose-alcuronium and Sepharose-choline, respectively (Fig. 1).
The comparison of clinical value of RIA and IDR in diagnosis of AS could be established in 26 patients with AS to succinylcholine (N = 19), gallamine (N = 2), or alcuronium (N = 5) (Table I). The Sepharose-choline RIA was positive in eight cases (Table I). Only two of the five patients having AS to alcuronium had a positive Sepharosealcuronium RIA (Table II). No interference between the seric-IgE level and the RIA was observed, since no significant correlation was found between both parameters (r = 0.167; n = 15). Comparatively, the IDRs with the incriminated drug were positive in 18 of the 26 patients. Both tests were positive in 10 cases. As far as the incriminated myorelaxant is studied, all the patients with negative IDRs had negative RIAs. No relationship was found between the reactive dilution for the skin and the results of the RIA (Fig.
748
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et al.
J ALLERGY CL,N. IMMUNOL. YWEMRER 1988
TABLE II. Cross-reactivity to alcuronium in 24 patients with anaphylaxis to succinylcholine gallamine (21, pancuronium (31, and vecuronium (3) Alcuronium Cases I ‘.? 3
4 5 6 7 8 11 12 14 15 16 17 18 19 20 21 27 28 29 31 32 33
Incriminated myorelaxant* C C C C
(2)
C C C
+ + +
C C
+
C C C C C C C G G
V V V P P P
+ + + + +
IDR (w/ml1
(161, _--..-. __-.-.--
__^.-..I..-_.X----. RIA (*I (%I
50 50 5 0 0
500 500 50
50
*Abreviations same as in Table I. Wpper limit of normal values same as in Table I
2). Considering all these patients, the diagnosis of anaphylaxis was established by IDR in 75% of cases and by RIA in 43.5% of cases. The cross-reactivity to alcuronium was evaluated in 18 patients with AS to succinylcholine or gallamine, and in six patients with anaphylaxis to pancuronium or vecuronium (Table II). The Sepharose-alcuronium RIA and the corresponding IDR were positive in 15 cases and in nine of 24 cases, respectively. The crossreactivity with succinylcholine was studied in four patients with anaphylaxis to alcuronium, and in six patients with anaphylaxis to pancuronium or vecuronium (Table III). The Sepharose-choline RIA and the IDR with succinylcholine were positive in six cases and in three cases of 10, respectively. When all patients are considered, the cross-reactivity was proved by the RIA and the corresponding IDR in 6 1% and 35%, respectively.
The sex ratio in favor of female subjects is well established.*, 6. ‘. 24 This has been confirmed in our
study in which 38 of the 34 were female patients. Fisher and More’ have postulated that the patients could be previously sensitized by cosmetics, food and drug additives, and industrial materials, such as house disinfectants that contain quateraary ammonium compounds. This hypothesis could explain the predominance of female patients and the fact that anaphylaxis may occur without any previous contact with myorelaxant drugs. In this study, the four patients that had never been anesthesized were female subjects. The symptoms of atopy have been frequenly noticed by other investigators. ‘36,‘. I5 It was observed in 33% of cases in our study. The diagnosis olf AS from myorelaxant drugs depends mainly on IDR.S, ‘323**‘-*’ The positivity ,of the IDRs to an antigen relies on the bridging of two molecules of specific IgE by a divalent or a muItivalent antigen. In the general case of drugs, which are small monovalent haptens, a binding with carrier proteins is needed. However, skin reactions may be observed with divalent haptens, as Levine and Redmond% have demonstrated with benzylpenicilloyl haptens in this
Anaphylaxis
VOLUME 82 NUMBER 5, PART 1
to muscle
relaxants
30
749
B
A
. . ti # e.
10
p: .
. ------------------
. . .
2
I 0.5
1 5
50
I so0
I
n*gativa
0.01
0.1
1
10
100
n*gative
(W/ml)
( W4 INTRADERYAL
: . . ---------------_--------
REACTION
INTRADERMAL
REACTION
FIG. 2. Comparison of seric-specific IgE and mast cell-bound specific IgE to myorelaxants, as determined by RIA and IDR. A, IDR to alcuronium versus RIA to alcuronium in five patients with AS to alcuronium. B, IDR to succinylcholine (n = 18) and gallamine (n = 2) versus RIA to choline in 20 patients with AS to one or the other myorelaxant.
case. The distance between the epitopes must be at least 4.5 A, and the optimal distance varies from 8 up to 13 A. Myorelaxants are divalent molecules, the epitope of which is the quatemary ammonium ion.” Gallamine is trivalent, and succinylcholine, alcuronium, and pancuronium are divalent. Vecuronium is monovalent and contains a tertiary azote, but multimolecular complexes in solution could provide a multivalent structure. The distance between the ammonium quatemary ions fits the findings of Levine and Redmond? 10.7 A for ~tubocurarine and 11.1 A for pancuronium. 29 According to Fisher, 5 Vervloet et a1.,6 Moneret-Vautrin et al. ,9, 23 and Laxenaire et al.,‘O the sensitivity of IDR is in order of 70% to 98%. The highest sensitivity is observed when the test is repeated from 6 months up to 2 years later. The IDR remains positive during several years after the AS.*, z 23 The technique must be carried out very
carefully: intradermal injections with serial dilutions no
750
Moneret-Vautrin
et al.
TABLE III. Cross-reactivity to succinylcholine pancuronium (3), and vecuronium (3)
in 10 patients with AS to alcuronium
(4),
Siuccinylcholine --.-_-Cases 22 23 25 26 27 28 29 31 32 33
Incriminated myorelaxant* A A A A V V V P P P
IDR
(2)
RIA choline7
t&ml)
+ -
rw (0 :r,
i IO
T + + +.-
+ +
(-cl
100 loo
+ -
(3.41 !O Z? +.13.s t (9.7; i3.2; f2..5! ii.3; t.3 2 (O.Xi -_- _l__-
*Abreviations same as in Table I. fUpper limit of normal values same as in Table I.
two molecules have a closed structure that includes choline residues. We observed lower uptake of specific IgE on the Sepharose-alcuronium solid phase than on the Sepharose-choline solid phase in the present study. However, only four patients having anaphylactoid reaction against alcuronium have been studied, and this did not permit any comparison. In a recent evaluation of RIA, we have found an uptake of specific IgE on Sepharose-alcuronium as high as the uptake observed by Baldo and Fisher” with the same protocol.3’ The cross-reactivity was first demonstrated by cases of clinical reactions to a muscle relaxant in patients who had experienced an AS to another muscle relaxant.32 In our study, patients 27 and 29 had an AS in 1985 with vecuronium. They had not been previously injected with this drug, since vecuronium was available only in 1985, and their last general anesthesia had been performed in 1975. Consequently, they were sensitized to another muscle relaxant.33 It appears important to determine the spectrum of cross-reaction for individual patients, either by RIA or by IDR for predicting whether drugs might be safe for each patient having experienced an AS with one myorelaxant. The cross-reactivity is related to the common structural features of these drugs, all of which contain quaternary ammonium ions. Nevertheless, the specificity of the antibodies varies in different patients, ranging from a strong specificity to one substance, without cross-reactivity, to a weak specificity with a strong cross-reactivity, according to inhibition assays in different studies from Harle et al.20.*I In our series, the in vitro cross-reactivity was dem-
onstrated in 61% of cases. The important fact is that the diagnosis of AS to a myorelaxant may be obtained, owing to this phenomenon of cross-reactivity, even with another myorelaxant coupled to Sepharose. This was the case in eight patients having experienced an AS with pancuronium or vecuronium. Five patients had positive RIA with alcuronium- or choline-coupled Sepharose . It must be emphasized, however, that the in vitro cross-reactivity is not a predictive test for the clinical risk of AS. A number of drugs without muscle relaxant activity, such as neostigmine, are able to react with the antimyomlaxant IgE antibodies,” but the corresponding patients do not react with these drugs. “. ” The common feature shared by those drugs is the existence of quaternary ammonium radicals. As a positive skin test demonstrates the crosslinking of mast cell-bound specific IgE by a convenient antigen, it might be assumed that it predicts the risk of anaphylaxis with this substance. Different authors have used skin tests to study the cross-reactivity. ‘3 **. 23 In this study, the incidence of positive skin tests is 35%, much lower than the in vitro cross-reactivity (61%). In 16 patients whose skin mast cells are sensitized by antisuccinylcholine IgE, only six have positive -skin tests with alcuronium . This discrepancy may be explained by the different conformational features of the two molecules. The succinylcholine molecule is a linear and flexible one; therefore, it affords variable distances between NH, epitopes. This would favor the brid&g of mast cellbound IgE antibodies. Conversely, the alcuronium
VOLUME 82 NUMBER 5, PART 1
molecule is cyclic and more rigid.34 Didier et a1.3s have demonstrated that myorelaxants with a rigid backbone, such as pancuronium, are less active than flexible molecules, such as suxamethonium, in initiating mediator release. Second, some specific IgE for succinylcholine might have a specificity enlarged to choline residues. It may be hypothesized that the specific conformational structure for the epitope NH4, in the antibody site, is too deeply located to be accessible to NH, ions on the surface of the alcuronium molecule. In the case of positive skin tests to a myorelaxant, a clinical risk of the use of the myorelaxant is encountered, and the drug should be avoided. In the case of negative skin tests, it might be assumed that there is no clinical risk. In fact, we tested this hypothesis in case 1. The young girl had a severe AS to succinylcholine in 1975, and IDR remained positive several times, until 1985, when RIA was strongly positive. She had to undergo an abdominal surgery, and myorelaxants were needed. IDR was negative to vecuronium, even in pure solution. With her informed consent, vecuronium was used and was well tolerated. However, the histamine-releasing effect of pure myorelaxants may alter the nonspecific reactivity of the skin, and the prediction of a safe use of a myorelaxant will probably need, in the future, other methods, such as histamine release. The increasing incidence of ASS to myorelaxants leads to the need of sensitive and specific tests. The RIAs with choline-coupled Sepharose and alcuronium-coupled Sepharose provide good results. Because of the phenomenon of cross-reactivity, they are useful, even when other myorelaxants, such as vecuronium and pancuronium, are incriminated. In some cases, either RIA or IDR reactions are positive. These results indicate the usefulness of both tests in the same patient. The cross-reactivity is a frequent phenomenon in AS to myorelaxants. The need of tests to predict the clinical risk is obvious. Further insights will be provided by comparative studies of skin tests, leukocyte histamine release, and in vitro inhibition assays. ’ REFERENCES 1. Clarke RSJ. Clinical features and changing trends in hypersensitivity reactions. AM Fr Anesth Reanim 1985;4: 146-5 1. 2. Laxenaire MC, Moneret-Vautrin DA, Vervloet D. The French experience of anaphylactoid reactions. In: Sage DJ, ed. International anesthesiology clinics: anaphylactoid reactions in anaesthesia. Boston: Little, Brown, 1985145-60. 3. Laxenaire MC, Mane1 J, Borgo J, Moneret-Vat&in DA. Facteurs de risque d’histamino-IiWration: etude prospective dam une population anesthesi&e de 23 444 patients. Ann Fr Anesth Reanim 1985;4:1.58-66. 4. Moneret-Vautrhr DA, GriIliat JP, Lhorte D, Laxenaire MC. Test de d&granulation des hasophiles humains: inter& dam le
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Duration of the sllppressive ant ressants on histamine wheai-and-flare reactions in hv Kamineni S. Rao, MO, Prem K. Menon, MD, Bettina C. tfilman, C. Simon Sebastian, MO, and Lee Bairnsfather, PhD !Chreveport,
MD, La.
The antihistaminic properties of the tricyclic antidepressants have been recognized since these compounds were first developed. Antidepressants, which are equally effective for treating depression or used in the treatment of chronic urticaria, have varying in vitro antihistaminic properties. We compared the duration of H,-receptor blockade by two tricyclic antidepressants, doxepin (the most potent antihistamine) and desipramine (the least potent antihistamine}, in a single dose, double-blind, noncrossover study. After baseline prick test with histamine phosphate 1: 1000 by Multitest (Lincoln Diagnostics, Decatur, Ill.), the suppression of cutaneous histamine-induced wheal-and-flare responses were measured daily for 7 days in 33 healthy volunteers who were randomly administered a single 25 mg dose of oral a’esipramine or doxepin. Significant d#ierences in the suppression of the wheal-and-fire responses to histamine between the two drugs were noted (p < 0.05) during the first 3 days. Desipramine suppressed the wheal for 2 days andyare for I day. Doxepin suppressed the wheal for 4 days and flare for 6 days. Our results suggest doxepin should be withheld for at least 7 aIays before allergy skin testing. (J ALLERGY CLIN IUMUNOL 1988;82:752-7.)
From the Pulmonary/Allergy Section of the Department of Pediatrics and Departments of Psychiatry and Biometry, Louisiana State University School of Medicine, Shreveport, La. Presented as a poster at the Forty-third Annual Meeting of the American Academy of Allergy and Immunology, Washington, DC, Feb. 19-25, 1987. Received for publication March 20, 1987. Accepted for publication May 11, 1988. Reprint requests: Bettina C. Hilman, MD, 1501 Kings Highway, Shreveport, LA 71130-3932.
752
The cutaneous wheal-and-flare response to allergens compared to negative saline control in the presence of positive wheal-and-flare response induced by histamines has been the basic diagnostic tool to identify IgE response to specific allergens in atupic individuals. The pataent referred for testing to specific allergens may be receiving one or more drugs that could interfere with allergen- and/or his&mineinduced wheal-and-flare responses in the skin. It is
France
Thirty-four patients (31 female and three male patients) with a previous anaphylactoid shock to muscle relaxants were investigated. The seric antimyorelaxant IgE was detected by radioimmunoassay (RIA), and the results were compared to intradermal test (IDR) reactions to dilutions of the commercial drugs. The RIA was carried out with a Sepharose-myorelaxant solid phase and anti-IgE “‘I-labeled IgG. The results corresponded to the percentage of labeled anti-IgE bound on the solid phase. The RIA with Sepharose-alcuronium and Sepharose-choline was estimated positive from determination with normal sera (n = 12) when bound IgE was >I .O% and I .5%, respectively. The RIA and IDR were positive in 43.5% and 758, respectively, of the cases, with a concordance of 66%. One test at least was positive in 79.4% of the cases. No correlation was found between IgE seric levels and the RIA nor between the cutaneous sensitivity and the RIA. Cross-reactivity with Sepharose-choline and Sepharose-alcuronium was observed in 50%, and it was demonstrated by IDR in only 34.2%. The RIA demonstrated the specificity of IgE to quaternary ammonium compounds as myorelaxant drugs. The positive IDR revealed the bridging of mast cell-bound spectfic IgE, depending on structural conditions, such as the flexibility of the molecules or the variable spectficity of the antibodies, restricted to quaternary ammonium ions or enlarged to a broader part of the incriminated molecules. (J ALLERGY CLIN IMMUNOL 1988;82:745-52.)
The incidence of ASs in general anesthesia is 0.67% with death in 0.05%.lm3 The following muscle relaxants are predominantly implicated: D-tubocurarine, alcuronium, gallamine, succinylcholine, pancuronium, vecuronium, and, more recently, atracurium.4-” Alcuronium is mostly involved in Australia, whereas ASS are mostly provoked by suxamethonium in France. *, 3. 9, ‘* The histamine-releasing property of these drugs is well-known. In some cases, a nonspecific activation of the alternate pathway of complement has been speculated, but the anaphylactic mechanism is more frequent. ‘345 The passive cutaneous
From *Service d’Immuno-Allergologie, Mtdecine D, Nancy, **Laboratoire de Biochimie Medicale et Wdiatrique - Faculte de MCdecine, Nancy, and ***Dtpartement d’Anesth&iologie, Hapital Central, Nancy, France. Received for publication Nov. 17, 1986. Accepted for publication April 23, 1988. Reprint requests: D. A. Moneret-Vautrin, MD, Faculte de M&ktine, B.P. 184, 54505 Vkndoeuvre, Les, Nancy Cedex, France.
Abbreviations used IDR: Intradermal test RIA: Radioimmunoassay
AS: Anaphylactic shock
anaphylaxis test is often positive, and its reactivity is abolished by heating serum 2 hours at 56” C.5-8 Leukocyte histamine release is inhibited by preincubation with an anti-IgE serum. I3 The presence of sericspecific IgE against myorelaxants has been demonstrated by Baldo and FisheP’* and Harle et alL9-*’ All molecules of the muscle relaxants share quaternary ammonium radicals that should be the common epitopes. This could explain the cross-reactivity among those drugs. In patients with AS to one myorelaxant, the number of drugs implicated in the crossreactivity is variable when IDRs are used.*‘. 23 The comparison of IDRs and RIAs has revealed that the in vitro cross-reactivity is not related to the clinical 745
746
Moneret-Vautrin
J. ALLERGY Ciirv IMMUNCL. NOV’MBER :x48
et al.
Sepharose -ethanolamine
iepharose 3lcuronium
Sspharosa choline
vecuronium have similar structures except the presence of two quatemary ammonium in pancuronium, whereas vccuronium hasonly one quatemary ammonium and one tertiary. The diagnosis has been establishedfrom 6 tc; 12 weeks after the AS in 28 casesand from 3 to 10 year.” xfttcr the AS in six cases.
------. .
The IDRs were performed in the back with serial dliutlons of commercial solutions and 0.03 to 0.05 ml peg injection. The IDR was considered positive when the diameter of ihc: wheal reached 10 mm 1.5minutes after Ihe injection ’
RIA . . : .. . : .. . : l
.
:
.
Controls
ln=ZO)
c
patients
lnz26)
FIG. 1. Percentage of uptake of ‘251-labeled anti-lgE onto Sepharose-choline and Sepharose-alcuronium in the presence of control sera (*I. The unspecific adsorption of the tracer was also tested for sera from patients (0) with Sapharose-ethanolamine instead of the drug-solid phase. The upper normal limit of uptake percentage (- -- -) was estimated, respectively, to 1.0% and to 2.0% for Sepharose-alcuronium and Sepharose-choline.
Specific antidrug IgE was detected in serum by an RlA in which the drug (alcuronium or choline) was r~ovalentlv coupled to Sepharose. Drug-Sepharose
coupling
procedure.
PATWWS
AND METHODS
Thirty-four patients (31 female and three male patients, aged from 16 to 67 years) have been included in the study. The myorelaxant and number of patients implicated were succinykholine, 19; gallamine, 2; alcuronium, 5; pancnronium, 5; and vecuronium, 3. The first two myorelaxants have a closed chemical structure, since two methylcholine residuesare included in succinylcholineand three ethylcholine residuesin the structure of gallamine. Pancuronium and
oi
solid drug phase was washed successively with threefold the volume of 0.1 mol/L of sodium carbonate, pW 12, ISfold the volume of 0.1 mol/L of sodium borate buffer, pH 9.0, and incubated (overnight with 10 ml of 1 mol:L of ethanolamine at pH 9.0 and at 35” C. Then, it was washed again with 15-fold the volume of 0.1 moliL of sodium borate buffer, pH 9.~0. 15fold the volume of 0 05 mol/ I, of sodium acetate, pH 4.0, and 15fold of 0.154 mol ‘L of NaCl containing 0.02% NaN, (wt/vol). The efficiency of’ the coupling procedure was estimated to about 20% and 25% for alcuronium dichloride and choline. respectively.
This was calculated, from drug content of risk of anaphylactoid reactions.*’ In the present study, we have determined seric-specific IgE against muscle relaxants by IDR and RIA in 34 patients who had an AS to succinylcholine ( 19)) gallamine (2)) alcuronium (5), pancuronium (4), and vecuronium (4). Our purpose was (1) to compare the clinical value of RIA and IDR in the diagnosis of AS to two myorelaxants, succinylcboline and alcuronium, and (2) to evaluate the accuracy of both tests in cross-reactivity to other muscle relaxants, since both tests investigate different aspects of the IgE mechanism.
One Barn
epoxy-activated Sepharose6B (PharmaciaFine Chemicals, Uppsala, Sweden) was swollen in distilled water and WC-. cessivelywashed with tenfold the volume of 0. I moli L of sodium carbonate, pH 12, containing 0.5 mol/L of NaCI. The gel was incubated with 70 mg of either alcuronium dichloride (Hoffmann-LaRoche, Basel, Switzerland) or choline chloride (Sigma Chemical Co., St. Louis, MO.) during 18 hours under mild. rotative agitation and at .3tr” C. The
the supernatant
before and after the coupling with ultraviolet spectrophotometry. Radioimmunoassay. Each test was duplicated. ‘4 volume of 50 ~1 of drug phase was incubated overnight with 50 p,I of serum at room temperature. The gel was washed three time with 3.0 ml of 0.1 mol/L of sodium phosphate buffer, pH 7.4, containing 0.154 mol/L of NaCl, 0.02% bovine serum albumin (wtivol), and Tween 20, and incubated during 12 hours with 50 ~1 of ‘*Wabeled anti-IgE (Pharmacia). It was then washed three times again with the sodium phosphate solution. The presence of seric-specific antidrug IgE was attested from the percentage of bound labeled antiIgE determined by counting the radioactivity. .The nonspecific binding of seric IgE was tested with Sepharoscethanolamine instead of the solid drug phase, and the nonspecific binding of anti-IgE was tested by subrtltution of serum with a 0.1 mol /L of sodium phosphate buffer solution containing 2% bovine serum albumin (wt/vol).
RESULTS The cardiovascular collapse was observed in all cases with cutaneous reactions involving erythema or
VOLUME 82 NUMBER 5, PART 1
Anaphylaxis
TABLE I. IDR and RIA to the incriminated (19), gallamine (2), and alcuronium (5)
myorelaxant
in 26 patients
with
AS
to muscle
Incriminated myorelaxant*
1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16
17 18 19 20 21 22 23 ’ 24 25 26
I
C C C C C C C C C C C C C C C C C C C G G
A A A A A
hE (KUI/L) ND 572 190 203 80 ND ND 303 57 ND 39 80 ND ND 55 21 ND 27 ND 15 12 367 870 ND 921 ND
I* 1
IDR (pglml)
(1) (10) (10) (10) (10) (100) (1W (1W ++ + ++ + + + + + + + -
(0.1) (10) (0.01) (10) (10) (10) (10) (10)
(0.5) (50)
747
to succinylcholine
Incriminated
Case
relaxants
myorelaxant RlAt (.c)
(%I
+ -
(25.9) (1.5) (1.5) ND (1.0) (1.1)
+ + + -
+ + + + + + -
(1.8) (13.4) (0.4) (0.3)
(1.6) (2.4) (3.1)
(1.2) (3.3) (0.5) (2.5) (28.8) (16.4) (1.0) (0.67) (1.1) (1.1) (0.7) (0.9)
(0.8)
ND = Not done. *C = Succinylcholine; G = gallamine; A = alcuronium. YThe radioimmunoassay was carried out with Sepharose-choline for the diagnosis of anaphylaxis to succinylcholine and gallamine, and with Sepharose-alcuronium for the diagnosis of anaphylaxis to alcuronium. The upper limit of normal values was estimated, respectively, to 2.0% and to 1 .O% for the Sepharose-choline and sepharose-akuronium RIA.
Quincke’s edema in 80% of cases and bronchospasm in 39% of cases. Previous anesthesia was reported in 23 cases. Four patients had never been anesthetized. Two patients had never received vecuronium that elicited the AS. Atopy was observed in 33% of cases and confirmed by IDR with inhalants; 24% of patients had extrinsic asthma in childhood. Three other subjects have an infraclinical atopy, revealed by positive skin tests to inhalants and a high level of seric IgE (367,772, and 921 KUl/L). In the 20 control subjects, the percentage of binding was 0.6 + 0.2%, 0.5 + 0.2%, and 1.0 + 0.5%, respectively, with Sepharose-ethanolamine, sepharose-alcuronium, and Sepharose-choline. The upper normal limit was estimated to 1 .O% and to 2.0% for Sepharose-alcuronium and Sepharose-choline, respectively (Fig. 1).
The comparison of clinical value of RIA and IDR in diagnosis of AS could be established in 26 patients with AS to succinylcholine (N = 19), gallamine (N = 2), or alcuronium (N = 5) (Table I). The Sepharose-choline RIA was positive in eight cases (Table I). Only two of the five patients having AS to alcuronium had a positive Sepharosealcuronium RIA (Table II). No interference between the seric-IgE level and the RIA was observed, since no significant correlation was found between both parameters (r = 0.167; n = 15). Comparatively, the IDRs with the incriminated drug were positive in 18 of the 26 patients. Both tests were positive in 10 cases. As far as the incriminated myorelaxant is studied, all the patients with negative IDRs had negative RIAs. No relationship was found between the reactive dilution for the skin and the results of the RIA (Fig.
748
Moneret-Vautrin
et al.
J ALLERGY CL,N. IMMUNOL. YWEMRER 1988
TABLE II. Cross-reactivity to alcuronium in 24 patients with anaphylaxis to succinylcholine gallamine (21, pancuronium (31, and vecuronium (3) Alcuronium Cases I ‘.? 3
4 5 6 7 8 11 12 14 15 16 17 18 19 20 21 27 28 29 31 32 33
Incriminated myorelaxant* C C C C
(2)
C C C
+ + +
C C
+
C C C C C C C G G
V V V P P P
+ + + + +
IDR (w/ml1
(161, _--..-. __-.-.--
__^.-..I..-_.X----. RIA (*I (%I
50 50 5 0 0
500 500 50
50
*Abreviations same as in Table I. Wpper limit of normal values same as in Table I
2). Considering all these patients, the diagnosis of anaphylaxis was established by IDR in 75% of cases and by RIA in 43.5% of cases. The cross-reactivity to alcuronium was evaluated in 18 patients with AS to succinylcholine or gallamine, and in six patients with anaphylaxis to pancuronium or vecuronium (Table II). The Sepharose-alcuronium RIA and the corresponding IDR were positive in 15 cases and in nine of 24 cases, respectively. The crossreactivity with succinylcholine was studied in four patients with anaphylaxis to alcuronium, and in six patients with anaphylaxis to pancuronium or vecuronium (Table III). The Sepharose-choline RIA and the IDR with succinylcholine were positive in six cases and in three cases of 10, respectively. When all patients are considered, the cross-reactivity was proved by the RIA and the corresponding IDR in 6 1% and 35%, respectively.
The sex ratio in favor of female subjects is well established.*, 6. ‘. 24 This has been confirmed in our
study in which 38 of the 34 were female patients. Fisher and More’ have postulated that the patients could be previously sensitized by cosmetics, food and drug additives, and industrial materials, such as house disinfectants that contain quateraary ammonium compounds. This hypothesis could explain the predominance of female patients and the fact that anaphylaxis may occur without any previous contact with myorelaxant drugs. In this study, the four patients that had never been anesthesized were female subjects. The symptoms of atopy have been frequenly noticed by other investigators. ‘36,‘. I5 It was observed in 33% of cases in our study. The diagnosis olf AS from myorelaxant drugs depends mainly on IDR.S, ‘323**‘-*’ The positivity ,of the IDRs to an antigen relies on the bridging of two molecules of specific IgE by a divalent or a muItivalent antigen. In the general case of drugs, which are small monovalent haptens, a binding with carrier proteins is needed. However, skin reactions may be observed with divalent haptens, as Levine and Redmond% have demonstrated with benzylpenicilloyl haptens in this
Anaphylaxis
VOLUME 82 NUMBER 5, PART 1
to muscle
relaxants
30
749
B
A
. . ti # e.
10
p: .
. ------------------
. . .
2
I 0.5
1 5
50
I so0
I
n*gativa
0.01
0.1
1
10
100
n*gative
(W/ml)
( W4 INTRADERYAL
: . . ---------------_--------
REACTION
INTRADERMAL
REACTION
FIG. 2. Comparison of seric-specific IgE and mast cell-bound specific IgE to myorelaxants, as determined by RIA and IDR. A, IDR to alcuronium versus RIA to alcuronium in five patients with AS to alcuronium. B, IDR to succinylcholine (n = 18) and gallamine (n = 2) versus RIA to choline in 20 patients with AS to one or the other myorelaxant.
case. The distance between the epitopes must be at least 4.5 A, and the optimal distance varies from 8 up to 13 A. Myorelaxants are divalent molecules, the epitope of which is the quatemary ammonium ion.” Gallamine is trivalent, and succinylcholine, alcuronium, and pancuronium are divalent. Vecuronium is monovalent and contains a tertiary azote, but multimolecular complexes in solution could provide a multivalent structure. The distance between the ammonium quatemary ions fits the findings of Levine and Redmond? 10.7 A for ~tubocurarine and 11.1 A for pancuronium. 29 According to Fisher, 5 Vervloet et a1.,6 Moneret-Vautrin et al. ,9, 23 and Laxenaire et al.,‘O the sensitivity of IDR is in order of 70% to 98%. The highest sensitivity is observed when the test is repeated from 6 months up to 2 years later. The IDR remains positive during several years after the AS.*, z 23 The technique must be carried out very
carefully: intradermal injections with serial dilutions no
750
Moneret-Vautrin
et al.
TABLE III. Cross-reactivity to succinylcholine pancuronium (3), and vecuronium (3)
in 10 patients with AS to alcuronium
(4),
Siuccinylcholine --.-_-Cases 22 23 25 26 27 28 29 31 32 33
Incriminated myorelaxant* A A A A V V V P P P
IDR
(2)
RIA choline7
t&ml)
+ -
rw (0 :r,
i IO
T + + +.-
+ +
(-cl
100 loo
+ -
(3.41 !O Z? +.13.s t (9.7; i3.2; f2..5! ii.3; t.3 2 (O.Xi -_- _l__-
*Abreviations same as in Table I. fUpper limit of normal values same as in Table I.
two molecules have a closed structure that includes choline residues. We observed lower uptake of specific IgE on the Sepharose-alcuronium solid phase than on the Sepharose-choline solid phase in the present study. However, only four patients having anaphylactoid reaction against alcuronium have been studied, and this did not permit any comparison. In a recent evaluation of RIA, we have found an uptake of specific IgE on Sepharose-alcuronium as high as the uptake observed by Baldo and Fisher” with the same protocol.3’ The cross-reactivity was first demonstrated by cases of clinical reactions to a muscle relaxant in patients who had experienced an AS to another muscle relaxant.32 In our study, patients 27 and 29 had an AS in 1985 with vecuronium. They had not been previously injected with this drug, since vecuronium was available only in 1985, and their last general anesthesia had been performed in 1975. Consequently, they were sensitized to another muscle relaxant.33 It appears important to determine the spectrum of cross-reaction for individual patients, either by RIA or by IDR for predicting whether drugs might be safe for each patient having experienced an AS with one myorelaxant. The cross-reactivity is related to the common structural features of these drugs, all of which contain quaternary ammonium ions. Nevertheless, the specificity of the antibodies varies in different patients, ranging from a strong specificity to one substance, without cross-reactivity, to a weak specificity with a strong cross-reactivity, according to inhibition assays in different studies from Harle et al.20.*I In our series, the in vitro cross-reactivity was dem-
onstrated in 61% of cases. The important fact is that the diagnosis of AS to a myorelaxant may be obtained, owing to this phenomenon of cross-reactivity, even with another myorelaxant coupled to Sepharose. This was the case in eight patients having experienced an AS with pancuronium or vecuronium. Five patients had positive RIA with alcuronium- or choline-coupled Sepharose . It must be emphasized, however, that the in vitro cross-reactivity is not a predictive test for the clinical risk of AS. A number of drugs without muscle relaxant activity, such as neostigmine, are able to react with the antimyomlaxant IgE antibodies,” but the corresponding patients do not react with these drugs. “. ” The common feature shared by those drugs is the existence of quaternary ammonium radicals. As a positive skin test demonstrates the crosslinking of mast cell-bound specific IgE by a convenient antigen, it might be assumed that it predicts the risk of anaphylaxis with this substance. Different authors have used skin tests to study the cross-reactivity. ‘3 **. 23 In this study, the incidence of positive skin tests is 35%, much lower than the in vitro cross-reactivity (61%). In 16 patients whose skin mast cells are sensitized by antisuccinylcholine IgE, only six have positive -skin tests with alcuronium . This discrepancy may be explained by the different conformational features of the two molecules. The succinylcholine molecule is a linear and flexible one; therefore, it affords variable distances between NH, epitopes. This would favor the brid&g of mast cellbound IgE antibodies. Conversely, the alcuronium
VOLUME 82 NUMBER 5, PART 1
molecule is cyclic and more rigid.34 Didier et a1.3s have demonstrated that myorelaxants with a rigid backbone, such as pancuronium, are less active than flexible molecules, such as suxamethonium, in initiating mediator release. Second, some specific IgE for succinylcholine might have a specificity enlarged to choline residues. It may be hypothesized that the specific conformational structure for the epitope NH4, in the antibody site, is too deeply located to be accessible to NH, ions on the surface of the alcuronium molecule. In the case of positive skin tests to a myorelaxant, a clinical risk of the use of the myorelaxant is encountered, and the drug should be avoided. In the case of negative skin tests, it might be assumed that there is no clinical risk. In fact, we tested this hypothesis in case 1. The young girl had a severe AS to succinylcholine in 1975, and IDR remained positive several times, until 1985, when RIA was strongly positive. She had to undergo an abdominal surgery, and myorelaxants were needed. IDR was negative to vecuronium, even in pure solution. With her informed consent, vecuronium was used and was well tolerated. However, the histamine-releasing effect of pure myorelaxants may alter the nonspecific reactivity of the skin, and the prediction of a safe use of a myorelaxant will probably need, in the future, other methods, such as histamine release. The increasing incidence of ASS to myorelaxants leads to the need of sensitive and specific tests. The RIAs with choline-coupled Sepharose and alcuronium-coupled Sepharose provide good results. Because of the phenomenon of cross-reactivity, they are useful, even when other myorelaxants, such as vecuronium and pancuronium, are incriminated. In some cases, either RIA or IDR reactions are positive. These results indicate the usefulness of both tests in the same patient. The cross-reactivity is a frequent phenomenon in AS to myorelaxants. The need of tests to predict the clinical risk is obvious. Further insights will be provided by comparative studies of skin tests, leukocyte histamine release, and in vitro inhibition assays. ’ REFERENCES 1. Clarke RSJ. Clinical features and changing trends in hypersensitivity reactions. AM Fr Anesth Reanim 1985;4: 146-5 1. 2. Laxenaire MC, Moneret-Vautrin DA, Vervloet D. The French experience of anaphylactoid reactions. In: Sage DJ, ed. International anesthesiology clinics: anaphylactoid reactions in anaesthesia. Boston: Little, Brown, 1985145-60. 3. Laxenaire MC, Mane1 J, Borgo J, Moneret-Vat&in DA. Facteurs de risque d’histamino-IiWration: etude prospective dam une population anesthesi&e de 23 444 patients. Ann Fr Anesth Reanim 1985;4:1.58-66. 4. Moneret-Vautrhr DA, GriIliat JP, Lhorte D, Laxenaire MC. Test de d&granulation des hasophiles humains: inter& dam le
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751
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.I A!LFRGY
,ilN iMMUhjOL. ‘J:?VSMi3ER 1988
31. Gueant JL, Kamel L, Moneret-Vautrin DA. Widmer S, Laxenaire MC, Nicolas JP. Methode radio-immunologique de dCtection des IgE sp&ifiques g I’alcuronium. L\rtn Fr Anssth Reanim 1986:5:570-3. 32. Fisher M, Chan MCY. Anaphylaxis to both aecamethonium and suxamethonium. Anesth Intensive Care 1982; I If: 1.52-S. 33. Moneret-Vautrin DA, Mouton C, Widmer S. Anaphylaxic cmi&e avec le vCcuronium. Ann Fr Anesth Reanim 1984;3:467. 34. Vervloet D, Amaud A, Didier A, Furstoss A. Charpin D. Allergy to quatemary ammonium cationic compounds. in: Reed CE. Proceedings of the XII International Congress of Allergology and Clinical Immunology. St Louis: CV Mosby Co. 1986:6Y-74. 35. Didier A, Cador D, Bongrand P. Furstoss R. Fourneroll P, Senft M, Philip-Joet F, Charpin D, Charpin .I. Vervloet D, Role of the quaternary ammonium ion determinants in allergy to muscle relaxzmts. .I ALLERGY CLIN IM~~UNOI 19X7-795’%-
84.
Duration of the sllppressive ant ressants on histamine wheai-and-flare reactions in hv Kamineni S. Rao, MO, Prem K. Menon, MD, Bettina C. tfilman, C. Simon Sebastian, MO, and Lee Bairnsfather, PhD !Chreveport,
MD, La.
The antihistaminic properties of the tricyclic antidepressants have been recognized since these compounds were first developed. Antidepressants, which are equally effective for treating depression or used in the treatment of chronic urticaria, have varying in vitro antihistaminic properties. We compared the duration of H,-receptor blockade by two tricyclic antidepressants, doxepin (the most potent antihistamine) and desipramine (the least potent antihistamine}, in a single dose, double-blind, noncrossover study. After baseline prick test with histamine phosphate 1: 1000 by Multitest (Lincoln Diagnostics, Decatur, Ill.), the suppression of cutaneous histamine-induced wheal-and-flare responses were measured daily for 7 days in 33 healthy volunteers who were randomly administered a single 25 mg dose of oral a’esipramine or doxepin. Significant d#ierences in the suppression of the wheal-and-fire responses to histamine between the two drugs were noted (p < 0.05) during the first 3 days. Desipramine suppressed the wheal for 2 days andyare for I day. Doxepin suppressed the wheal for 4 days and flare for 6 days. Our results suggest doxepin should be withheld for at least 7 aIays before allergy skin testing. (J ALLERGY CLIN IUMUNOL 1988;82:752-7.)
From the Pulmonary/Allergy Section of the Department of Pediatrics and Departments of Psychiatry and Biometry, Louisiana State University School of Medicine, Shreveport, La. Presented as a poster at the Forty-third Annual Meeting of the American Academy of Allergy and Immunology, Washington, DC, Feb. 19-25, 1987. Received for publication March 20, 1987. Accepted for publication May 11, 1988. Reprint requests: Bettina C. Hilman, MD, 1501 Kings Highway, Shreveport, LA 71130-3932.
752
The cutaneous wheal-and-flare response to allergens compared to negative saline control in the presence of positive wheal-and-flare response induced by histamines has been the basic diagnostic tool to identify IgE response to specific allergens in atupic individuals. The pataent referred for testing to specific allergens may be receiving one or more drugs that could interfere with allergen- and/or his&mineinduced wheal-and-flare responses in the skin. It is